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Extracorporeal blood purification treatment options for COVID-19: The role of immunoadsorption

  • Tuğçe Nur Yiğenoğlu
    Affiliations
    University of Health Sciences, Ankara Oncology Training and Research Hospital, Department of Hematology & Apheresis Unit, Ankara, Turkey
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  • Turgay Ulas
    Affiliations
    Near East University, School of Medicine, Department of Internal Medicine, Division of Hematology, Nicosia, Cyprus
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  • Mehmet Sinan Dal
    Affiliations
    University of Health Sciences, Ankara Oncology Training and Research Hospital, Department of Hematology & Apheresis Unit, Ankara, Turkey
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  • Serdal Korkmaz
    Affiliations
    University of Health Sciences, Kayseri Training and Research Hospital, Department of Hematology & Apheresis Unit, Kayseri, Turkey
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  • Mehmet Ali Erkurt
    Affiliations
    Inönü University, School of Medicine, Department of Internal Medicine, Division of Hematology & Apheresis Unit, Malatya, Turkey
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  • Fevzi Altuntaş
    Correspondence
    Corresponding author at: Ankara Yıldırım Beyazıt Medical Faculty, Department of Internal Medicine, Division of Hematology, Bilkent-Cankaya, 06800, Ankara, Turkey.
    Affiliations
    University of Health Sciences, Ankara Oncology Training and Research Hospital, Department of Hematology & Apheresis Unit, Ankara, Turkey

    Ankara Yıldırım Beyazıt University, School of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey
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      Abstract

      The activation of the innate and adaptive immune systems by SARS-CoV-2 causes the release of several inflammatory cytokines, including IL-6. The inflammatory hypercytokinemia causes immunopathological changes in the lungs including vascular leakage, and alveolar edema. As a result of these changes in the lungs, hypoxia and acute respiratory distress syndrome occur in patients with COVID-19. Even though there are clinical trials on the development of therapeutics and vaccines, there are currently no licensed vaccines or therapeutics for COVID-19. Pharmacological approaches have shown poor results in sepsis-like syndromes caused by the hypercytokinemia. Suppressing the cytokine storm is an important way to prevent the organ damage in patients with COVID-19. Extracorporeal blood purification could be proposed as an adjunctive therapy for sepsis, aiming to control the associated dysregulation of the immune system, which is known to protect organ functions. Several extracorporeal blood purification therapies are now available, and most of them target endotoxins and/or the cytokines and aim improving the immune response. For this purpose, plasmapheresis and immunoadsorption may be an important adjunctive treatment option to manage the complications caused by cytokine storm in critically ill patients with COVID-19.

      Keywords

      1. Introduction

      The highly pathogenic Coronaviruses (CoVs), Severe Acute Respiratory Syndrome CoV-1 (SARS-CoV-1) and Middle East Respiratory Syndrome CoV (MERS-CoV), infect the lower respiratory tract and cause severe pneumonia, sometimes leading to fatal acute lung injury [
      • Kuiken T.
      • Fouchier R.A.
      • Schutten M.
      • Rimmelzwaan G.F.
      • van Amerongen G.
      • van Riel D.
      • et al.
      Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome.
      ,
      • Peiris J.S.
      • Lai S.T.
      • Poon L.L.
      • Guan Y.
      • Yam L.Y.
      • Lim W.
      • et al.
      SARS study group. Coronavirus as a possible cause of severe acute respiratory syndrome.
      ,
      • Zaki A.M.
      • van Boheemen S.
      • Bestebroer T.M.
      • Osterhaus A.D.
      • Fouchier R.A.
      Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.
      ]. At the end of 2019, a cluster of patients with viral pneumonia was started to be observed in Wuhan, China [
      • Li Q.
      • Guan X.
      • Wu P.
      • Wang X.
      • Zhou L.
      • Tong Y.
      • et al.
      Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia.
      ]. Soon after, researchers revealed that the cause of these pneumonia cases were the 2019 Novel CoV (2019-nCoV) [
      • Zhu N.
      • Zhang D.
      • Wang W.
      • Li X.
      • Yang B.
      • Song J.
      • et al.
      China novel coronavirus investigating and research team. A novel coronavirus from patients with pneumonia in China, 2019.
      ]. On February 11, 2020, the disease was officially named as COVID-19 and 2019-nCoV was named as SARS-CoV-2 [
      • World Health Organization Press Conference
      The world health organization (WHO) has officially named the disease caused by the novel coronavirus as COVID-19.
      ,
      • Wu Z.
      • McGoogan J.M.
      Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the chinese center for disease control and prevention.
      ]. The disease was declared a pandemic by the WHO on March 11, 2020. As of 23 April 2020, worldwide, there have been 2,510,177 confirmed cases of COVID-19, including 172,241 deaths, as reported to WHO [
      • World Health Organization Press Conference
      The world health organization (WHO) has officially named the disease caused by the novel coronavirus as COVID-19.
      ].
      In a study from China, it was reported that, among all patients with COVID-19, 5% had critical disease (respiratory or multiorgan failure), 14 % had severe disease (>50 % lung involvement on imaging within 24–48 hours, or hypoxia) and 81 % had mild symptoms [
      • Wu Z.
      • McGoogan J.M.
      Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the chinese center for disease control and prevention.
      ]. The rate of severe and critical disease or mortality may vary according to geographic location. In mid-March, in Italy, the estimated case fatality rate was 7.2 % whereas it was 0.9 % in South Korea. There are some factors that have impact on the rate of case fatalities such as, proportion of elderly population in that country, previous exposure to other CoV variants and the quality of healthcare system. For example, the median age of patients with COVID-19 was 64 years in Italy, whereas in Korea the median age was in the 40 s [
      • Grasselli G.
      • Pesenti A.
      • Cecconi M.
      Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: early experience and forecast during an emergency response.
      ,
      • Onder G.
      • Rezza G.
      • Brusaferro S.
      Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy.
      ,
      • KCDC
      Updates on COVID-19 in Korea.
      ]. In a report from China, including 44,500 patients with confirmed COVID-19, 87 % of patients were between 30 and 79 years old. In this report, older age and/or the presence of any comorbidity was also associated with increased mortality. The case fatality rate was 8% in patients aged 70–79 years whereas it was 15 % in patients 80 years or older [
      • Wu Z.
      • McGoogan J.M.
      Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the chinese center for disease control and prevention.
      ].
      The activation of innate and adaptive immune system by SARS-CoV-2 causes the release of several inflammatory cytokines, including IL-6 [
      • Leiva-Juárez M.M.
      • Kolls J.K.
      • Evans S.E.
      Lung epithelial cells: therapeutically inducible effectors of antimicrobial defense.
      ,
      • Knudsen L.
      • Ochs M.
      The micromechanics of lung alveoli: structure and function of surfactant and tissue components.
      ,
      • Brune K.
      • Frank J.
      • Schwingshackl A.
      • Finigan J.
      • Sidhaye V.K.
      Pulmonary epithelial barrier function: some new players and mechanisms.
      ]. IL-6 induces proliferation and differentiation of B cells. While stimulating Th17 cells. IL-6 inhibits regulatory T cell (Treg), and promotes CD4 T cell response [
      • Jones B.E.
      • Maerz M.D.
      • Buckner J.H.
      IL-6: a cytokine at the crossroads of autoimmunity.
      ,
      • Kimura A.
      Kishimoto T. IL-6: regulator of Treg/Th17 balance.
      ,
      • Bettelli E.
      • Carrier Y.
      • Gao W.
      • Korn T.
      • Strom T.B.
      • Oukka M.
      • et al.
      Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
      ]. Additionally, high levels of expression of other cytokines such as IL-1B, IFN-γ, IP-10 and monocyte chemoattractant protein-1 may activate the T-helper type 1 cell response. The severity of the disease is correlated with the increased serum levels of IL-2R and IL-6 in patients with COVID-19 [
      • Chen L.
      • Liu H.G.
      • Liu W.
      • Liu J.
      • Liu K.
      • Shang J.
      • et al.
      [Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia].
      ]. In one study, the researchers showed that the COVID-19 patients in the intensive care unit (ICU) had higher levels of granulocyte colony-stimulating factor, IP-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1A, and TNF-α compared to COVID-19 patients in general wards [
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ]. The inflammatory hypercytokinemia causes immunopathological changes in the lungs including vascular leakage, and alveolar edema. As a result of these changes in the lungs, hypoxia and acute respiratory distress syndrome (ARDS) occur in patients with COVID-19 [
      • Drosten C.
      • Seilmaier M.
      • Corman V.M.
      • Hartmann W.
      • Scheible G.
      • Sack S.
      • et al.
      Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection.
      ,
      • Lew T.W.
      • Kwek T.K.
      • Tai D.
      • Earnest A.
      • Loo S.
      • Singh K.
      • et al.
      Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome.
      ]. In COVID-19, the median time from first symptom to dyspnea was 5 days, to hospital admission was 7 days, and to ARDS was 8 days [
      • Arentz M.
      • Yim E.
      • Klaff L.
      • Lokhandwala S.
      • Riedo F.X.
      • Chong M.
      • et al.
      Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State.
      ,
      • Danzi G.B.
      • Loffi M.
      • Galeazzi G.
      • Gherbesi E.
      Acute pulmonary embolism and COVID-19 pneumonia: a random association?.
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • Zhu F.
      • Liu X.
      • Zhang J.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      ].
      In severe disease, if the pharmacological treatment is not efficacious, extracorporeal treatment options seem to be a good aproach. In order to prevent progression of the pathologic changes in COVID-19, inflammatory cytokines should be reduced [
      • Bouadma L.
      • Lescure F.X.
      • Lucet J.C.
      • Yazdanpanah Y.
      • Timsit J.F.
      Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists.
      ,
      • Wan S.
      • Yi Q.
      • Fan S.
      • Lv J.
      • Zhang X.
      • Guo L.
      • et al.
      Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP).
      ]. Therapeutic options for hypercytokinemia include steroids, selective cytokine inhibition (anakinra, tocilizumab), JAK inhibition, and blood purification treatments (BPTs). Tocilizumab is a recombinant humanized anti-IL-6 receptor IgG1 antibody [
      • Xu X.
      • Han M.
      • Li T.
      • et al.
      Effective treatment of severe COVID-19 patients with tocilizumab.
      ]. The efficacy of tocilizumab has been shown in patients with COVID-19 and elevated IL-6 levels in a multicentre randomised controlled trial in China [
      • Chinese Clinical Trial Registry
      A multicenter, randomized controlled trial for the efficacy and safety of tocilizumab in the treatment of new coronavirus pneumonia (COVID-19).
      ]. The (BPTs) including plasma exchange (PE), immunoadsorption (IA), perfusion, blood/plasma filtration, etc., can eliminate inflammatory factors from the blood and reduce the effects of hypercytokinemia. The BPTs can be used in the early and middle phases of the disease in severe and critical patients with COVID-19 [
      • Xu K.
      • Cai H.
      • Shen Y.
      • Ni Q.
      • Chen Y.
      • Hu S.
      • et al.
      [Management of corona virüs disease-19 (COVID-19): the Zhejiang experience].
      ]. Through application of specific devices BPTs may also be used to support lungs, heart, kidneys, and liver [
      • Ronco C.
      • Navalesi P.
      • Vincent J.L.
      Coronavirus epidemic: preparing for extracorporeal organ support in intensive care.
      ]. However, the use of extracorporeal BPTs remains controversial because of the conflicting results observed in randomized controlled studies [
      • Monard C.
      • Rimmelé T.
      • Ronco C.
      Extracorporeal blood purification therapies for Sepsis.
      ].
      As mentioned above, in organ dysfunction syndromes, when pharmacological treatments are not available or efficacious, mechanical ventilation along with hemodynamic support and BPTs seem to be the only possible strategy [
      • Bouadma L.
      • Lescure F.X.
      • Lucet J.C.
      • Yazdanpanah Y.
      • Timsit J.F.
      Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists.
      ]. Historically, the efficacy of BPT in removing pathogenic antibodies or cytokines has been proven in a various of diseases, but not in COVID-19 patients [
      • Li G.
      • Zhang L.
      • Ren H.
      • Huang B.
      • Mao C.
      • Zhou A.
      Clearance of magnesium in peritoneal Dialysis patients: a single-center study.
      ,
      • Bucciarelli S.
      • Espinosa G.
      • Cervera R.
      • Erkan D.
      • Gómez-Puerta J.A.
      • et al.
      European Forum on Antiphospholipid Antibodies. Mortality in the catastrophic antiphospholipid syndrome: causes of death and prognostic factors in a series of 250 patients.
      ]. Therefore, in this review, we aimed to discuss the role of different BPT options and focus on the IA methods to remove both endotoxins and cytokines in patients with COVID-19.

      2. Therapeutic plasma exchange (TPE)

      TPE removes inflammatory cytokines, stabilizes endothelial membranes, and improves the hypercoagulable state. Although previous studies suggest that the use of TPE in sepsis is safe, there are only limited evidence as to whether TPE is beneficial for sepsis, and not studied in ARDS [
      • Knaup H.
      • Stahl K.
      • Schmidt B.M.W.
      • Idowu T.O.
      • Busch M.
      • Wiesner O.
      • et al.
      Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers.
      ,
      • Keith P.
      • Day M.
      • Perkins L.
      • Moyer L.
      • Hewitt K.
      • Wells A.
      A novel treatment approach to the novel coronavirus: an argument for the use of therapeutic plasma exchange for fulminant COVID-19.
      ,
      • Jörres A.
      Blood purification in sepsis.
      ]. In the largest randomized controlled study evaluating the efficacy of TPE in sepsis, a lower 28-day mortality rate was shown in the patients who had TPE performed compared to the patients who received standard therapy. However, with additional TPE, when controlled for other contributing factors, no significant difference was found regarding the mortality rate between 2 groups [
      • Grasselli G.
      • Pesenti A.
      • Cecconi M.
      Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: early experience and forecast during an emergency response.
      ]. Previous reports including a total of 194 patients showed insufficient evidence of benefit using TPE as an adjunctive therapy in patients with sepsis [
      • Rimmer E.
      • Houston B.L.
      • Kumar A.
      • Abou-Setta A.M.
      • Friesen C.
      • Marshall J.C.
      • et al.
      The efficacy and safety of plasma exchange in patients with sepsis and septic shock: a systematic review and meta-analysis.
      ]. The American Society for Apheresis (ASFA) recommends that the decision about the use of TPE in the treatment of sepsis with multiorgan failure should be individualized because the optimum role of apheresis therapy is not established [
      • Chwartz J.
      • Padmanabhan A.
      • Aqui N.
      • Balogun R.A.
      • Connelly-Smith L.
      • Delaney M.
      • et al.
      Guidelines on the use of therapeutic apheresis in clinical practice-evidence-Based approach from the writing committee of the american society for apheresis: the seventh special issue.
      ].
      The effect of TPE has not been studied in patients infected with SARS-CoV-1 and MERS. However, there are a limited number of studies on the use of TPE in patients with COVID-19 to reduce the levels of inflammatory cytokines. Ma et al. ([
      • Ma J.
      • Xia P.
      • Zhou Y.
      • Liu Z.
      • Zhou X.
      • Wang J.
      • et al.
      Potential effect of blood purification therapy in reducing cytokine storm as a late complication of critically ill COVID-19.
      ]) reported 3 cases with critically ill patients with COVID-19. 1 patient was treated with plasmapheresis, the others had undergone continuous renal replacement treatment. After performing plasmapheresis, clinical condition was improved and the patient was extubated. Shi et al. ([
      • Shi H.
      • Zhou C.
      • He P.
      • Huang S.
      • Duan Y.
      • Wang X.
      • et al.
      Successful treatment of plasma exchange followed by intravenous immunogloblin in a critically ill patient with 2019 novel coronavirus infection.
      ]) reported a 50 year old critically ill patient with COVID-19 refractory to pharmacological treatment, who received TPE followed by intravenous immunoglobulin (IVIG) and showed that performing TPE prevented the progression of the disease and reduced the need for intensive supportive care [
      • Shi H.
      • Zhou C.
      • He P.
      • Huang S.
      • Duan Y.
      • Wang X.
      • et al.
      Successful treatment of plasma exchange followed by intravenous immunogloblin in a critically ill patient with 2019 novel coronavirus infection.
      ]. Limited case reports demonstrated beneficial effect of TPE in pateints with COVID-19, but whether or not this effect is seen after using TPE should be confirmed in controlled studies.

      3. Double-filtration plasmapheresis (DFPP)

      DFPP removes the immunoglobulin fraction from the serum selectively [
      • Tanabe K.
      Double-filtration plasmapheresis.
      ]. DFPP has been used for several indications such as hyperacute rejection in ABO-incompatible kidney transplantation, and in the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis with severe kidney dysfunction [
      • Cheng L.
      • Tang Y.Q.
      • Yi J.
      • Ren Q.
      • Yang X.Y.
      • Gou S.J.
      • et al.
      Double filtration plasmapheresis in the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis with severe kidney dysfunction.
      ,
      • Chauvel F.
      • Reboul P.
      • Cariou S.
      • Aglae C.
      • Renaud S.
      • Trusson R.
      • et al.
      Use of double filtration plasmapheresis for the treatment of acquired thrombocytopenic thrombotic purpura.
      ]. In the literature, DFPP has not yet been performed in sepsis and ARDS, and also in COVID-19 yet, and how it will affect the course of the disease is not known.

      4. Immunoadsorption

      IA is a safe and well-tolerated treatment that can provide both biochemical and clinically objective improvements by selectively removing cytokines in patients with severe sepsis. It has been suggested that hemoadsorption devices could also adsorb leukocytes, mainly activated monocytes and neutrophils, in addition to cytokines and/or endotoxins. When used in patients with severe sepsis, it was shown that IA reduced inflammatory markers, norepinephrine requirement, the duration of ventilation and ICU stay [
      • Schefold J.C.
      • von Haehling S.
      • Corsepius M.
      • Pohle C.
      • Kruschke P.
      • Zuckermann H.
      • et al.
      A novel selective extracorporeal intervention in sepsis: immunoadsorption of endotoxin, interleukin 6, and complement-activating product 5a.
      ,
      • Rimmelé T.
      • Kaynar A.M.
      • McLaughlin J.N.
      • Bishop J.V.
      • Fedorchak M.V.
      • Chuasuwan A.
      • et al.
      Leukocyte capture and modulation of cell-mediated immunity during human sepsis: an ex vivo study.
      ]. Therefore, IA may be an important adjunctive treatment option to reduce the complications caused by hypercytokinemia in critically ill patients with COVID-19. Worldwide, more than 200 critically ill patients with COVID-19 have been treated with IA. In previous studies, in severe and critical patients with COVID-19 in ICUs, a significant benefit was observed with the use of hemoperfusion with cartridges containing highly biocompatible sorbents and microporous resins [
      • Wang D.
      • Hu B.
      • Hu C.
      • Zhu F.
      • Liu X.
      • Zhang J.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      ,
      • Ronco C.
      • Reis T.
      • De Rosa S.
      Coronavirus Epidemic and Extracorporeal Therapies in Intensive Care: si vis pacem para bellum.
      ,
      • Ankawi G.
      • Fan W.
      • Pomarè Montin D.
      • Lorenzin A.
      • Neri M.
      • Caprara C.
      • et al.
      A new series of sorbent devices for multiple clinical purposes: current evidence and future directions.
      ]. Although there is no randomised study, the Italian Society of Nephrology and ERA-EDTA recommended the use of IA in severe COVID-19 patients receiving Continuous Renal Replacement Therapy [

      Brescia Renal Covid Task Force: Alberici F et al., Gestıone Del Pazıente In Dialisi E Con Trapıanto Di Rene In Corso Di Infezione Da Coronavirus COVID-19, published March 18th by the Italian Society of Nephrology and by ERA-EDTA.

      ]. Also, the recent National Guidelines on adult COVID-19 patients from Panama recommend IA therapy [

      Asociación Panameña de Medicina Critica y Terapia Intensiva, Guías Nacionales De Atencıón De Pacientes Adultos COVID-19 VERSION 2.0, published on March 22nd.

      ]. On the 13 April 2020, the United States Food and Drug Administration (FDA) issued an Emergency Use Authorization for emergency use of IA to treat patients 18 years of age or older with confirmed COVID-19 admitted to the ICU with confirmed or imminent respiratory failure [

      FDA. U.S. FDA Grants CytoSorb® Emergency Use Authorization for Use in Patients with COVID-19 Infection. Retrieved from https://www.prnewswire.com/news-releases/us-fda-grants-cytosorb-emergency-use-authorization-for-use-in-patients-with-covid-19-infection-301039293.html (Access date 22.04.2020).

      ].
      In conclusion, ARDS is responsible for the majority of deaths in patients with COVID-19. Hypercytokinemia is responsible from the majority of symptoms in severe and critical patients. Therefore, reducing the levels of inflammatory cytokines is an important way to prevent the organ damage. In severe disease, if the pharmacological treatment is not efficacious, extracorporeal BPT options seem to be a good approach to reduce the levels of cytokines. Randomized prospective clinical trials are needed in order to show the efficacy of these aproaches.

      Declaration of Competing Interest

      All authors declare that they do not have any potential conflict of interest that could inappropriately influence the present study.

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      1. Brescia Renal Covid Task Force: Alberici F et al., Gestıone Del Pazıente In Dialisi E Con Trapıanto Di Rene In Corso Di Infezione Da Coronavirus COVID-19, published March 18th by the Italian Society of Nephrology and by ERA-EDTA.

      2. Asociación Panameña de Medicina Critica y Terapia Intensiva, Guías Nacionales De Atencıón De Pacientes Adultos COVID-19 VERSION 2.0, published on March 22nd.

      3. FDA. U.S. FDA Grants CytoSorb® Emergency Use Authorization for Use in Patients with COVID-19 Infection. Retrieved from https://www.prnewswire.com/news-releases/us-fda-grants-cytosorb-emergency-use-authorization-for-use-in-patients-with-covid-19-infection-301039293.html (Access date 22.04.2020).